IMCIVREE 10 mg/ml solution for injection

IMCIVREE is indicated for the treatment of obesity and the control of hunger associated with genetically confirmed Bardet-Biedl syndrome (BBS), loss-of-function biallelic pro-opiomelanocortin (POMC), including PCSK1, deficiency or biallelic leptin receptor (LEPR) deficiency in adults and children 2 years of age and above.

IMCIVREE should be prescribed and supervised by a physician with expertise in obesity with underlying genetic aetiology.

Posology

POMC, including PCSK1, deficiency and LEPR deficiency

Adult population and children from 12 to 17 years of age

For adults and children from 12 to 17 years of age, the starting dose is a 1 mg once daily subcutaneous injection for 2 weeks. After 2 weeks, if setmelanotide is well tolerated (see section 4.4), the dose can be increased to a 2 mg once daily subcutaneous injection (Table 1). If dose escalation is not tolerated, patients may maintain administration of the 1 mg once daily dose.

If additional weight loss is desired in adult patients, the dose can be increased to a 2.5 mg once daily subcutaneous injection. If the 2.5 mg once daily dose is well tolerated, the dose may be increased to 3 mg once daily (Table 1).

In patients from 12 to 17 years of age, if weight remains above the 90^th percentile with the 2 mg once daily subcutaneous injection and additional weight loss is desired, the dose may be increased to 2.5 mg with a maximum dose of 3 mg once daily (Table 1).

Table 1 Dose titration in adults and paediatric patients from 12 to 17 years of age

Paediatric population (children from 6 to < 12 years of age)

For paediatric patients from 6 to < 12 years of age, the starting dose is a 0.5 mg once daily subcutaneous injection for 2 weeks. If tolerated after 2 weeks, the dose can be increased to 1 mg once daily. If dose escalation is not tolerated, paediatric patients may maintain administration of the 0.5 mg once daily dose. If the 1 mg dose is tolerated after 2 weeks, the dose may be increased to 2 mg once daily. If weight remains above the 90^th percentile with the 2 mg once daily subcutaneous injection and additional weight loss is desired, the dose may be increased to 2.5 mg once daily (Table 2).

Table 2 Dose titration for paediatric patients from 6 to < 12 years of age

Paediatric population (children from 2 to < 6 years of age)

For paediatric patients from 2 to < 6 years of age, the dose titration in Table 3 should be followed.

For paediatric patients from 2 to < 6 years of age, the starting dose is a 0.5 mg once daily subcutaneous injection for 2 weeks. If the 0.5 mg starting dose is not tolerated, the dose should be reduced to 0.25 mg (0.025 ml) once daily. If the 0.25 mg once daily dose is tolerated, dose titration should be continued.

Table 3 Dose titration for paediatric patients from 2 to < 6 years of age

The prescribing physician should periodically assess response to setmelanotide treatment. In growing children, the impact of weight loss on growth and maturation should be evaluated (see section 4.4).

Weight loss and control of hunger associated with setmelanotide can be maintained as long as the treatment is continued uninterrupted. If treatment is discontinued, or if compliance to the dosing regimen is not maintained, symptoms of POMC and LEPR deficiency obesity will return.

Bardet‑Biedl syndrome

Adult population and children from 16 to 17 years of age

For adults and children from 16 to 17 years of age, the dose titration in Table 4 should be followed.

Table 4 Dose titration in adults and paediatric patients from 16 to 17 years of age

If the 2 mg starting dose is not tolerated, the dose should be reduced to 1 mg (0.1 ml) once daily. If the 1 mg once daily dose is tolerated, dose titration should be continued.

Following the starting dose, if a subsequent dose is not tolerated, the dose should be reduced to the previous dose level. If the reduced dose is tolerated, dose titration should be continued.

Paediatric population (children from 6 to < 16 years of age)

For paediatric patients from 6 to < 16 years of age, the dose titration in Table 5 should be followed.

Table 5 Dose titration for paediatric patients from 6 to < 16 years of age

If the 1 mg starting dose is not tolerated, the dose should be reduced to 0.5 mg (0.05 ml) once daily. If the 0.5 mg once daily dose is tolerated, the dose should be increased to 1 mg once daily and dose titration should be continued.

Following the starting dose, if a subsequent dose is not tolerated, the dose should be reduced to the previous dose level. If the reduced dose is tolerated, dose titration should be continued.

Paediatric population (children from 2 to < 6 years of age)

For paediatric patients from 2 to < 6 years of age, the dose titration in Table 6 should be followed.

For paediatric patients from 2 to < 6 years of age, the starting dose is a 0.5 mg once daily subcutaneous injection for 2 weeks. If the 0.5 mg starting dose is not tolerated, the dose should be reduced to 0.25 mg (0.025 ml) once daily. If the 0.25 mg once daily dose is tolerated, dose titration should be continued.

Table 6 Dose titration for paediatric patients from 2 to < 6 years of age

The prescribing physician should periodically assess response to setmelanotide treatment. In growing children, the impact of weight loss on growth and maturation should be evaluated (see section 4.4).

Weight loss and control of hunger associated with setmelanotide can be maintained as long as the treatment is continued uninterrupted. If treatment is discontinued, or if compliance to the dosing regimen is not maintained, symptoms of obesity and/or hunger in BBS will return.

Missed dose

If a dose is missed, the once daily regimen should be resumed at the dose prescribed with the next scheduled dose.

Special populations

Renal impairment

POMC, including PCSK1, deficiency and LEPR deficiency

For adults and children from 2 to 17 years of age with mild or moderate renal impairment (see section 5.2), no dose adjustments are necessary.

For adults and children from 12 to 17 years of age with severe renal impairment (see section 5.2), the dose titration in Table 7 should be followed.

Table 7 Dose titration in adults and paediatric patients from 12 to 17 years of age with severe renal impairment

If the 0.5 mg starting dose is not tolerated, the dose should be reduced to 0.25 mg (0.025 ml) once daily. If the 0.25 mg once daily dose is tolerated, dose titration should be continued.

Following the starting dose, if a subsequent dose is not tolerated, the dose should be reduced to the previous dose level. If the reduced dose is tolerated, dose titration should be continued.

For paediatric patients from 6 to < 12 years of age with severe renal impairment, the dose titration in Table 8 should be followed.

Table 8 Dose titration for paediatric patients from 6 to < 12 years of age with severe renal impairment

If the 0.25 mg starting dose is not tolerated, treatment should be discontinued.

Following the starting dose, if a subsequent dose is not tolerated, the dose should be reduced to the previous dose level. If the reduced dose is tolerated, dose titration should be continued.

Setmelanotide has not been studied in patients from 2 to < 6 years of age with severe renal impairment. Dose titration should be guided by tolerability (Table 9) and patients should be monitored closely.

Table 9 Dose titration for paediatric patients from 2 to < 6 years of age with severe renal impairment

If the 0.25 mg starting dose is not tolerated, treatment should be discontinued.

Following the starting dose, if a subsequent dose is not tolerated, the dose should be reduced to the previous dose level. If the reduced dose is tolerated, dose titration should be continued.

Setmelanotide has not been studied in patients with end-stage renal disease. Setmelanotide should not be administered to patients with end-stage renal disease (see section 5.2).

Bardet‑Biedl syndrome

For adults and children from 2 to 17 years of age with mild or moderate renal impairment (see section 5.2), no dose adjustments are necessary.

For adults and children from 16 to 17 years of age with severe renal impairment (see section 5.2), the dose titration in Table 10 should be followed.

Table 10 Dose titration in adults and paediatric patients from 16 to 17 years of age with severe renal impairment

If the 0.5 mg starting dose is not tolerated, the dose should be reduced to 0.25 mg (0.025 ml) once daily. If the 0.25 mg once daily dose is tolerated, dose titration should be continued.

Following the starting dose, if a subsequent dose is not tolerated, the dose should be reduced to the previous dose level. If the reduced dose is tolerated, dose titration should be continued.

For paediatric patients from 6 to < 16 years of age with severe renal impairment, the dose titration in Table 11 should be followed.

Table 11 Dose titration for paediatric patients from 6 to < 16 years of age with severe renal impairment

If the 0.25 mg starting dose is not tolerated, treatment should be discontinued.

Following the starting dose, if a subsequent dose is not tolerated, the dose should be reduced to the previous dose level. If the reduced dose is tolerated, dose titration should be continued.

Setmelanotide has not been studied in patients from 2 to < 6 years of age with severe renal impairment. Dose titration should be guided by tolerability (Table 12) and patients should be monitored closely.

Table 12 Dose titration for paediatric patients from 2 to < 6 years of age with severe renal impairment

If the 0.25 mg starting dose is not tolerated, treatment should be discontinued.

Following the starting dose, if a subsequent dose is not tolerated, the dose should be reduced to the previous dose level. If the reduced dose is tolerated, dose titration should be continued.

Setmelanotide has not been studied in patients with end‑stage renal disease. Setmelanotide should not be administered to patients with end‑stage renal disease (see section 5.2).

Hepatic impairment

Setmelanotide has not been studied in patients with hepatic impairment. Setmelanotide should not be administered to patients with hepatic impairment.

Paediatric population (< 2 years of age)

The safety and efficacy of setmelanotide in children less than 2 years of age has not yet been established. No data are available.

Elderly

Although no apparent age-related differences have been observed, data obtained from elderly patients 65 years of age and above is not sufficient to determine whether they respond differently from younger patients. There is no evidence indicating any special precautions are required for treating an elderly population (see section 5.2).

Method of administration

For subcutaneous use.

Setmelanotide should be injected once daily, at the beginning of the day (to maximise hunger reduction during awake period), without regard to the timing of meals.

Setmelanotide should be injected subcutaneously in the abdomen, alternating the abdominal area each day.

Prior to initiation of treatment, patients should be trained by their healthcare professional on proper injection technique, to reduce the risk of administration errors such as needle sticks and incomplete dosing. Refer to the package leaflet for complete administration instructions with illustrations.

Setmelanotide should be administered using the syringe volumes and needle gauges shown in Table 13.

Table 13 Administration syringe and needle gauge, by setmelanotide dose

See section 6.6 for instructions on handling IMCIVREE.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Skin monitoring

Setmelanotide may lead to generalised increased skin pigmentation and darkening of pre-existing nevi because of its pharmacologic effect (see sections 4.8 and 5.1). Full body skin examinations should be conducted annually to monitor pre-existing and new skin pigmentary lesions before and during treatment with setmelanotide.

Heart rate and blood pressure monitoring

Heart rate and blood pressure should be monitored as part of standard clinical practice at each medical visit (at least every 6 months) for patients treated with setmelanotide.

Prolonged penile erection

Spontaneous penile erections have been reported in clinical studies with setmelanotide (see section 4.8). Patients who have a penile erection lasting longer than 4 hours should be instructed to seek emergency medical attention for potential treatment of priapism.

Depression

In clinical studies, depression has been reported in patients treated with setmelanotide (see section 4.8).

Patients with depression should be monitored at each medical visit during treatment. Consideration should be given to discontinuing treatment if patients experience suicidal thoughts or behaviours.

Paediatric population

The prescribing physician should periodically assess response to setmelanotide treatment. In growing children, the impact of weight loss on growth and maturation should be evaluated. The prescribing physician should monitor growth (height and weight) using age- and sex-appropriate growth curves.

Excipients with known effect

Benzyl alcohol

This medicinal product contains 10 mg benzyl alcohol in each ml. Benzyl alcohol may cause allergic reactions.

There is an increased risk due to accumulation of benzyl alcohol in young children (aged less than 3 years). Patients aged 2 years should be monitored for any sign of metabolic acidosis (tachycardia, rapid breathing, confusion) while under treatment.

Patients who are pregnant or breastfeeding should be advised of the potential risk from the excipient benzyl alcohol, which might accumulate over time and cause metabolic acidosis.

This medicinal product should be used with caution in patients with hepatic or renal impairment, because of the potential risk from the excipient benzyl alcohol which might accumulate over time and cause metabolic acidosis (see also section 4.2).

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium-free.”

No interaction studies have been performed.

In vitro studies showed that setmelanotide has low potential for pharmacokinetic interactions related to cytochrome P450 (CYP) transporters and plasma protein binding.

Pregnancy

There are no data from the use of setmelanotide in pregnant women.

Animal studies do not indicate direct harmful effects with respect to reproductive toxicity. However, administration of setmelanotide to pregnant rabbits resulted in decreased maternal food consumption leading to embryo-foetal effects (see section 5.3).

As a precautionary measure, IMCIVREE should not be started during pregnancy or while attempting to get pregnant as weight loss during pregnancy may result in foetal harm.

If a patient who is taking setmelanotide has reached a stable weight and becomes pregnant, consideration should be given to maintaining setmelanotide treatment as there was no proof of teratogenicity in the non-clinical data. If a patient who is taking setmelanotide and still losing weight gets pregnant, setmelanotide should either be discontinued, or the dose reduced while monitoring for the recommended weight gain during pregnancy. The treating physician should carefully monitor weight during pregnancy in a patient taking setmelanotide.

Patients who are pregnant should be advised of the potential risk from the excipient benzyl alcohol (see section 4.4).

Breast-feeding

It is unknown whether setmelanotide is excreted in human milk. A non-clinical study showed that setmelanotide is excreted in the milk of nursing rats. No quantifiable setmelanotide concentrations were detected in plasma from nursing pups (see section 5.3).

A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from IMCIVREE treatment taking into account the benefit of breastfeeding for the child and the benefit of treatment for the mother.

Patients who are breastfeeding should be advised of the potential risk from the excipient benzyl alcohol (see section 4.4).

Fertility

No human data on the effect of setmelanotide on fertility are available. Animal studies did not indicate harmful effects with respect to fertility.

IMCIVREE has no or only minor influence on the ability to drive and use machines, due to somnolence.

Summary of the safety profile

The most frequent adverse reactions are hyperpigmentation disorders (67%), injection site reactions (46%), nausea (36%), and headache (20%).

Tabulated list of adverse reactions

Adverse reactions obtained from clinical studies and post-marketing surveillance are listed below by MedDRA system organ class and frequency, following the frequency convention defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), and uncommon (≥ 1/1 000 to < 1/100).

Table 14 Adverse reactions

^a Grouped term (see “Description of selected adverse reactions” for full list of terms included).

^b Male-only denominator.

^c Female-only denominator.

Description of selected adverse reactions

Injection site reactions

Injection site reactions occurred in 46% of patients treated with setmelanotide. The most common injection site reactions were injection site erythema (28%), injection site pruritus (21%), injection site induration (16%), and injection site pain (16%). These reactions were typically mild, of short duration, and did not progress or lead to discontinuation of treatment. Injection site reactions include injection site‑associated events of erythema, pruritus, oedema, pain, induration, bruising, swelling, haemorrhage, hypersensitivity, haematoma, nodule, discolouration, irritation, warmth, hypertrophy and urticaria.

Hyperpigmentation disorders

Skin darkening was observed in 67% of patients treated with setmelanotide. This generally occurred within 2 to 3 weeks of starting treatment, continued for the duration of treatment, and resolved upon discontinuation of treatment. This darkening of skin is mechanism based, resulting from stimulation of the MC1 receptor. Hyperpigmentation disorders include skin hyperpigmentation, skin discolouration, ephelides, hair colour changes, lentigo, macule, nail discolouration, melanoderma, pigmentation disorder, solar lentigo, acanthosis nigricans, café au lait spots, nail pigmentation, pigmentation lip, tongue pigmentation, gingival hyperpigmentation and oral pigmentation.

Gastrointestinal disturbance

Nausea and vomiting were reported in 36% and 16% of patients, respectively, treated with setmelanotide. Nausea and vomiting generally occurred at initiation of treatment (within the first month), was mild and did not lead to discontinuation of treatment. These effects were transient and did not impact compliance with the recommended daily injections.

Penile erections

Spontaneous penile erection and erection increased were reported in 16% and 14% of male patients treated with setmelanotide, respectively; none of these patients reported prolonged erections (longer than 4 hours) requiring urgent medical evaluation (see section 4.4). This effect may be due to melanocortin 4 (MC4) receptor neural stimulation.

Immunogenicity

The observed incidence of anti-drug antibodies (ADA) to setmelanotide is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in setmelanotide pivotal studies with the incidence of ADA in other studies.

In patients with BBS or in patients with POMC, PCSK1, or LEPR deficiency, there is insufficient information to characterise the ADA response to setmelanotide and the effects of ADA on pharmacokinetics, pharmacodynamics, safety, or efficacy of setmelanotide.

In patients 2 to <6 years old, antibodies to setmelanotide were detected in one subject who was confirmed positive with a low titre and with no subsequent positive ADA (see Study 4 in section 5.1). Due to the small number of subjects positive to ADA to setmelanotide and limited sample size, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety or efficacy of setmelanotide is unknown.

A low incidence of antibodies to alpha-MSH has been detected in clinical studies to date. These include pre-existing antibodies to alpha-MSH as well as development of antibodies to alpha-MSH while on treatment. Due to this low incidence, there is insufficient data to characterise the effects of anti-alpha-MSH antibodies on the pharmacokinetics, pharmacodynamics, safety or efficacy of setmelanotide. None of the patients with POMC deficiency were confirmed to have antibodies to alpha-MSH.

Paediatric population

A total of 221 paediatric patients (n=12 aged 2 to < 6 years; n=72 aged 6 to < 12 years, n=137 aged 12 to < 18 years) have been exposed to setmelanotide, including 21 paediatric patients with POMC or LEPR deficiency obesity who participated in the pivotal clinical studies (n=7 aged 2 to < 6 years; n=6 aged 6 to < 12 years, n=8 aged 12 to < 18 years) and 33 paediatric patients with BBS (n=5 aged 2 to < 6 years; n=8 aged 6 to < 12 years, n=20 aged 12 to < 18 years). The frequency, type and severity of adverse reactions were similar in the adult and paediatric populations.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

The symptoms of setmelanotide overdose may include nausea and penile erection. In the event of overdose, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms. In cases of overdose, blood pressure and heart rate should be monitored regularly over 48 hours or as long as clinically relevant.

Pharmacotherapeutic group: anti-obesity preparations, excl. diet products, centrally acting anti-obesity products, ATC code: A08AA12

Mechanism of action

Setmelanotide is a selective MC4 receptor agonist. MC4 receptors in the brain are involved in regulation of hunger, satiety, and energy expenditure. In genetic forms of obesity associated with insufficient activation of the MC4 receptor, setmelanotide is believed to re-establish MC4 receptor pathway activity to reduce hunger and promote weight loss through decreased caloric intake and increased energy expenditure.

Pharmacodynamic effects

Skin pigmentation

Setmelanotide is a selective MC4 receptor agonist with less activity at the melanocortin 1 (MC1) receptor. The MC1 receptor is expressed on melanocytes, and activation of this receptor leads to accumulation of melanin and increased skin pigmentation independently of ultraviolet light (see sections 4.4 and 4.8).

Clinical efficacy and safety

POMC, including PCSK1, deficiency and LEPR deficiency

The safety and efficacy of setmelanotide for the treatment of POMC and LEPR deficiency obesity were established in 2 identically designed, 1‑year open‑label pivotal studies, each with a double‑blind, placebo‑controlled withdrawal period:

• Study 1 (RM-493-012) enrolled patients aged 6 years and above with genetically confirmed POMC (including PCSK1) deficiency obesity.

• Study 2 (RM-493-015) enrolled patients aged 6 years and above with genetically confirmed LEPR deficiency obesity.

In both studies, adult patients had a body mass index (BMI) of ≥ 30 kg/m². Weight in children was ≥ 95^th percentile using growth chart assessment.

Dose titration occurred over a 2- to 12‑week period, followed by a 10‑week open‑label treatment period. Patients who achieved at least a 5 kg weight loss (or at least 5% weight loss if baseline body weight was < 100 kg) at the end of the open‑label treatment period continued into a double‑blind, placebo‑controlled, withdrawal period lasting 8 weeks (4‑week placebo treatment and 4‑week setmelanotide treatment). Following the withdrawal sequence, patients re‑initiated active treatment with setmelanotide at the therapeutic dose for up to 32 weeks. Twenty‑one patients (10 in Study 1 and 11 in Study 2) have been treated for at least 1 year and are included in the efficacy analyses.

Additional supportive data were gathered in an investigator‑led study and an ongoing extension study.

Study 1 (RM-493-012)

In Study 1, 80% of patients with POMC deficiency obesity met the primary endpoint, achieving a ≥ 10% weight loss after 1 year of treatment with setmelanotide and 50% of patients with POMC deficiency obesity achieved a predefined clinically meaningful ≥ 25% improvement in hunger score from baseline at 1 year (Table 15).

Statistically significant and clinically meaningful mean percent decreases from baseline for body weight of 25.6% were reported for Study 1. Changes in hunger were assessed using a patient and caregiver questionnaire completed daily for 'most hunger over the last 24 hours' at 1 year for patients ≥ 12 years of age. Statistically significant and clinically meaningful mean percent decreases from baseline for hunger as a weekly average in the last 24 hours of 27.1% were reported for Study 1 (Table 16).

When treatment with setmelanotide was withdrawn in patients who had lost weight during the 10‑week open‑label period, these patients gained weight (Figure 1) and the mean hunger scores increased over the 4 weeks of placebo treatment.

Table 15 Proportion of patients achieving at least 10% weight loss and the proportion of patients achieving at least 25% improvement in daily hunger from baseline at 1 year in Study 1

Table 16 Percent change from baseline in weight and hunger at 1 year in Study 1

Figure 1 Percent body weight change from baseline by visit (Study 1 [N=9])

Study 2 (RM-493-015)

In Study 2, 46% of patients with LEPR deficiency obesity met the primary endpoint, achieving a ≥ 10% weight loss after 1 year of treatment with setmelanotide and 73% of patients with LEPR deficiency obesity achieved a predefined clinically meaningful ≥ 25% improvement in hunger score from baseline at 1 year (Table 17).

Statistically significant and clinically meaningful mean percent decreases from baseline for body weight of 12.5% were reported for Study 2. Changes in hunger were assessed using a patient and caregiver questionnaire completed daily for 'most hunger over the last 24 hours' at 1 year for patients ≥ 12 years of age. Statistically significant and clinically meaningful mean percent decreases from baseline for hunger as a weekly average in the last 24 hours of 43.7% were reported for Study 2 (Table 18).

When treatment with setmelanotide was withdrawn in patients who had lost weight during the 10‑week open‑label period, these patients gained weight (Figure 2) and the mean hunger scores increased over the 4 weeks of placebo treatment.

Table 17 Proportion of patients achieving at least 10% weight loss and the proportion of patients achieving at least 25% improvement in daily hunger from baseline at 1 year in Study 2

Table 18 Percent change from baseline in weight and hunger at 1 year in Study 2

Figure 2 Percent body weight change from baseline by visit (Study 2 [N=7])

Bardet‑Biedl syndrome

Study 3 (RM‑493‑023)

The safety and efficacy of setmelanotide for the treatment of patients aged 6 years and older with obesity due to BBS were assessed in a 1‑year clinical study with a 14‑week placebo‑controlled period (Study 3 [RM‑493‑023]). The study enrolled patients aged 6 years and above with obesity and BBS. Adult patients had a BMI of ≥ 30 kg/m². Paediatric patients had a BMI ≥ 97^th percentile for age and sex using growth chart assessments.

Eligible patients entered a 14‑week, randomized, double‑blind, placebo‑controlled treatment period (Period 1) followed by a 38‑week open‑label treatment period (Period 2) in which all patients received setmelanotide. To maintain the blind through Period 2, dose titration to a fixed dose of 3 mg was done during the first 2 weeks of both Period 1 and Period 2. Thirty-two patients have been treated for at least 1 year and are included in the efficacy analyses.

In Study 3, 35.7% of patients with BBS aged ≥ 12 years and 46.7% of patients with BBS aged ≥ 18 years met the primary endpoint, achieving a ≥ 10% weight loss after 1 year of treatment with setmelanotide (Table 19). The effect of setmelanotide on body weight in patients assessed by the investigator as cognitively impaired was similar to patients who were not cognitively impaired.

In Study 3, ~52 weeks of treatment with setmelanotide resulted in clinically meaningful reductions in BMI Z‑scores occurring in 100% of the BBS patients aged < 12 years, with consistent results observed in patients ≥ 12 and < 18 years of age. In patients aged < 18 years, the mean reduction from baseline in BMI Z‑score was 0.75 and the mean reduction from baseline in percent of the 95^th percentile for BMI for age and sex was 17.3%.

Patients 12 years and older who were able to self‑report their hunger, recorded their daily maximal hunger in a diary, which was then assessed by the Daily Hunger Questionnaire Item 2. Hunger was scored on an 11‑point scale from 0 (“not hungry at all”) to 10 (“hungriest possible”). Statistically significant and clinically meaningful mean percent decreases from baseline at 1 year for most/worst hunger of 30.5% were reported for Study 3 (Table 20).

Table 19 Body weight (kg) – proportion of all patients, patients with BBS aged ≥ 12 years and patients with BBS aged ≥ 18 years achieving at least 10% weight loss from baseline at 1 year (Study 3 [Full Analysis Set])

Table 20 Daily hunger scores – change from baseline at 1 year in all patients and patients with BBS aged ≥ 12 years (Study 3 [Full Analysis Set])

Supportive of the effect of setmelanotide on weight loss, there were general numeric improvements in cardiometabolic parameters, such as blood pressure, lipids, glycaemic parameters, and waist circumference.

Paediatric population

Study 4 (RM‑493‑033)

The safety and efficacy of setmelanotide for the treatment of patients from 2 to < 6 years of age with obesity due to POMC or LEPR deficiency or BBS were assessed in a 1‑year open-label, non-controlled study (Study 4 [RM‑493‑033]). The study enrolled patients from 2 to < 6 years of age with a BMI ≥ 97^th percentile for age and sex using growth chart assessments and a body weight of at least 15 kg at baseline.

Eligible patients entered the study and received setmelanotide. Twelve patients were enrolled in the study and are included in the efficacy analyses. Given the study design and small sample size, efficacy findings require careful consideration.

In Study 4, 85.7% of patients with POMC or LEPR deficiency obesity and 80.0% of the patients with BBS met the primary endpoint, achieving a ≥ 0.2 BMI Z-score reduction after 1 year of treatment with setmelanotide (Table 21). The mean percent change from baseline to Week 52 in BMI was ‑25.597% for patients with POMC or LEPR deficiency obesity and ‑9.719% for patients with BBS (Table 22).

Table 21 BMI Z‑score – proportion of all patients, patients with POMC or LEPR deficiency obesity, patients with BBS from 2 to < 6 years of age achieving at least 0.2 reduction in BMI Z‑score from baseline at 1 year (Study 4 [safety population])

Table 22 Percent change in BMI from baseline at 1 year (Study 4 [safety population])

In Study 4, ~52 weeks of treatment with setmelanotide resulted in a clinically meaningful reduction in BMI Z‑score of ‑5.185 for patients with POMC or LEPR deficiency obesity and ‑1.331 for patients with BBS. The mean reduction from baseline in percent of the 95^th percentile for BMI for age and sex was ‑47.595% for patients with POMC or LEPR deficiency obesity and ‑14.462% for patients with BBS.

In clinical studies, 54 of the patients treated with setmelanotide were from 2 to 17 years of age at baseline (21 patients with POMC, PCSK1 or LEPR deficiency and 33 patients with BBS). Overall, efficacy and safety in these younger patients showed similar trends as seen in older patients studied, with seemingly meaningful decreases in BMI demonstrated. In patients who had not yet completed their growth, a trend towards appropriate progression in pubertal development and increases in height were observed during the study period.

The European Medicines Agency has deferred the obligation to submit the results of studies with setmelanotide in one or more subsets of the paediatric population in treatment of appetite and general nutrition disorders (see section 4.2 for information on paediatric use).

The mean steady state setmelanotide C_max,ss, AUC_tau, and trough concentration for a 3 mg dose administered subcutaneously to otherwise healthy volunteers with obesity (N=6) once daily for 12 weeks were 37.9 ng/ml, 495 h*ng/ml, and 6.77 ng/ml, respectively. Steady‑state plasma concentrations of setmelanotide were achieved within 2 days with daily dosing of 1‑3 mg setmelanotide. The accumulation of setmelanotide in the systemic circulation during once‑daily dosing over 12 weeks was approximately 30%. Setmelanotide AUC and C_max increased proportionally following multiple‑dose subcutaneous administration in the proposed dose range (1‑3 mg).

A population PK model comprised of 410 subjects pooled from 11 studies was conducted. These subjects contributed 7 087 observations, of which 6 847 samples had quantifiable setmelanotide concentrations. The PK data were predominantly from 271 adults and 87 adolescents (from 12 to < 18 years of age). There were also 41 children from 6 to < 12 years of age and 11 children from 2 to < 6 years of age. The population consisted of 166 males and 244 females with ages ranging from 2 to 78 years (mean = 29.7 years) and weights ranging from 17.8 to 246 kg (mean = 113 kg). The pooled population included 329 subjects with POMC, PCSK1, or LEPR deficiency, BBS, or other rare genetic diseases of obesity (80.2%) and 81 subjects without POMC, PCSK1, or LEPR deficiency, BBS, or other rare genetic diseases of obesity (19.8%); all subjects without POMC, PCSK1 or LEPR deficiency, BBS, or other rare genetic diseases of obesity were adults.

Absorption

After subcutaneous injection of setmelanotide, steady-state plasma concentrations of setmelanotide increased slowly, reaching maximum concentrations at a median t_max of 8.0 hours after dosing. The absolute bioavailability following subcutaneous administration of setmelanotide has not been investigated in humans. Estimate of the inter‑individual variability (CV%) from the final population PK model was 39.9% (CL/F).

The PK of setmelanotide in patients with BBS was similar to that obtained in the population of patients with POMC, PCSK1, and LEPR deficiency, suggesting the disease state alone does not impact the PK of setmelanotide.

Distribution

The mean apparent volume of distribution of setmelanotide after subcutaneous administration of setmelanotide 3 mg once daily was estimated from the population PK model to be 75.2 L. Setmelanotide binding to human plasma protein is 79.1%.

In vitro experiments indicate that setmelanotide is not a substrate of OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.

In vitro data indicate that setmelanotide is very unlikely a P‑gp or BCRP substrate.

Biotransformation

Setmelanotide did not appear to be metabolised by rat, monkey, or human hepatic microsomes or hepatocytes, or kidney microsomes.

Elimination

The effective elimination half-life (t½) of setmelanotide was approximately 11 hours. The total apparent steady state clearance of setmelanotide following subcutaneous administration of 3 mg once daily was estimated from the population PK model to be 7.15 L/h.

Approximately 39% of the administered setmelanotide dose was excreted unchanged in urine during the 24‑hour dosing interval following subcutaneous administration of 3 mg once daily.

Linearity/non-linearity

Setmelanotide AUC and C_max increased approximately linearly with dose following multiple‑dose subcutaneous administration in the range of 0.5 mg to 5 mg.

Special populations

Paediatric population

Setmelanotide has been evaluated in paediatric patients (from 2 to 17 years of age). Simulations from the population PK analyses suggest slightly higher exposure in younger patients (who also have lower body weight) and provide support for the dosing regimen in patients 2 years and older.

Elderly population

Available data in a small sample of elderly patients 65 years of age and above suggest no marked changes in setmelanotide exposure with increased age. However, these data are too limited to draw definite conclusions.

Renal impairment

Pharmacokinetic analysis showed a 12%, 26%, and 49% lower clearance (CL/F) of setmelanotide in patients with mild, moderate, and severe renal impairment, respectively, as compared to patients with normal renal function.

POMC, including PCSK1, deficiency and LEPR deficiency

No dose adjustments for patients with mild (estimated glomerular filtration rate [eGFR] of 60‑89 ml/min/1.73 m²) or moderate renal impairment (eGFR of 30‑59 ml/min/1.73 m²) are needed. Dose adjustments are recommended for patients with severe renal impairment (eGFR 15‑29 ml/min/1.73 m²) (see section 4.2). Setmelanotide should not be administered to patients with end‑stage renal disease (eGFR < 15 ml/min/1.73 m²) (see section 4.2).

Bardet‑Biedl syndrome

No dose adjustments for patients with mild (estimated glomerular filtration rate [eGFR] of 60‑89 ml/min/1.73 m²) or moderate renal impairment (eGFR of 30‑59 ml/min/1.73 m²) are needed. Dose adjustments are recommended for patients with severe renal impairment (eGFR 15‑29 ml/min/1.73 m²) (see section 4.2). Setmelanotide should not be administered to patients with end‑stage renal disease (eGFR < 15 ml/min/1.73 m²) (see section 4.2).

Hepatic impairment

Setmelanotide is stable in human, rat, and monkey hepatocytes; therefore, a study in patients with hepatic impairment was not conducted. Setmelanotide should not be used in patients with hepatic impairment.

Body weight

Setmelanotide CL/F varied with body weight according to a fixed allometric relationship.

Gender

No clinically significant differences in the pharmacokinetics of setmelanotide were observed based on sex.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, carcinogenic potential, fertility, teratogenicity, or postnatal development.

A developmental reproduction study in rabbits revealed increases in embryo-foetal resorption and post‑implantation loss in pregnant rabbits treated with setmelanotide. These effects were attributed to extreme reductions in maternal food consumption related to the primary pharmacodynamic activity of setmelanotide. Similar reductions in food consumption and related embryo-foetal loss were not observed in a developmental reproduction study in rats. No teratogenic effects were observed in either species.

Dose‑related setmelanotide concentrations were observed in milk 2 hours after subcutaneous injection in the pre-weaning phase of a pre- and postnatal development study in rats. No quantifiable setmelanotide concentrations were detected in plasma from nursing pups at any dose.

In contrast to primates, variable cardiovascular effects, such as increased heart rate and blood pressure, were observed in rats and minipigs. The reason underlying those species differences remains unclear. In rat, the dose‑dependent effects of setmelanotide on heart rate and blood pressure were linked to an increase in sympathetic tone and they were found to progressively diminish upon repeated daily dosing.

Minimal cytoplasmic vacuolation related to the excipient mPEG‑DSPE was observed in the choroid plexus after chronic administration in adult rats and monkeys. Choroid plexus vacuolation was not observed in juvenile rats treated with setmelanotide/mPEG‑DSPE from post‑natal days 7 to 55 at 9.5‑times the human dose of mPEG-DSPE from 3 mg of setmelanotide on a mg/m²/day basis.

The available carcinogenicity data in Tg.rasH2 mice indicate that setmelanotide/mPEG‑DSPE does not pose a carcinogenic risk to patients, with a safety margin of 17 for setmelanotide based on AUC and a dose margin of 16 for mPEG DSPE on a mg/m²/day basis, at the clinical dose of 3 mg/day. Due to the lack of pro‑carcinogenic concern from the available non‑clinical and clinical data on setmelanotide, a 2‑year carcinogenicity study in rats has not been performed.

N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl- glycero-3-phosphoethanolamine sodium salt (mPEG-2000-DSPE)

Carmellose sodium

Mannitol

Phenol

Benzyl alcohol

Disodium edetate

Water for injections

Hydrochloric acid (for pH-adjustment)

Sodium hydroxide (for pH-adjustment)

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

3 years

After first opening

28 days or until the expiry date (whichever is earlier).

Do not store above 30 °C.

Chemical and physical in use stability has been demonstrated for 28 days at 2 °C to 30 °C.

From a microbiological point of view, once opened, the product may be stored for a maximum of 28 days at 2 °C to 30 °C. Other in-use storage times and conditions are the responsibility of the user.

Store in a refrigerator (2°C to 8°C). Do not freeze. Store in the original carton in order to protect from light.

Unopened vials may be kept at room temperature, not to exceed 30°C, for up to 30 days.

For storage conditions after first opening of the medicinal product, see section 6.3.

2R clear glass type I multidose vial with bromobutyl stopper and aluminium cap.

Pack size: 1 multidose vial.

IMCIVREE should be removed from the refrigerator approximately 15 minutes prior to administration. Alternatively, patients may warm the product prior to administration by rolling the vial gently between the palms of their hands for 60 seconds.

IMCIVREE should be inspected prior to each injection, and the solution should not be used if it is cloudy or contains particles.

If IMCIVREE is exposed to temperatures > 30 °C, it should be discarded and not used.

Always use a new syringe for each injection to prevent contamination.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.